Synthesis and anti-HIV-1 evaluation of new Sonogashira-modified Emivirine (MKC-442) analogues

DANEL K;JØRGENSEN PT;PEDERSEN EB;LA COLLA P;COLLU G;LODDO, ROBERTA

2009-01-01

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Abstract

The MKC-442 analogue 6-(3,5-dimethylbenzyl)-5-ethyluracil substituted with a (propargyloxo)-methyl group at N(1) has previously been found highly active against HIV-1. The C≡C bond in the substituent at N(1) is here utilized in a series of chemical reactions in order to develop new agents with higher activity against HIV-1-resistant mutants. The syntheses involved Pd-catalyzed C,C-coupling reactions, addition of disulfides, and click chemistry on the terminal C≡C bond as well as addition of bromine to the so formed internal C≡C bonds. Sonogashira coupling were performed with silylderivatized iodobenzyl alcohols which, after deprotection, were oxidized to aldehydes by means of IBX. The isomeric alcohol 37 was obtained in the Sonogashira reaction of propargyl alcohol with the N(1)-substituted (4-iodobenzyloxy)methyl derivative of the above mentioned uracil. Compound 37 turned out to be the most effective compound against problematic HIV-1 mutants. The general observation in the present work is that a combination of alkyne and aryl in the substituent at N(1) leads to highly active compounds against HIV-1.